Synthesis and biological assessment of diversely substituted furo[2,3-b]quinolin-4-amine and pyrrolo[2,3-b]quinolin-4-amine derivatives, as novel tacrine analogues |
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Authors: | Martins Carla Carreiras M Carmo León Rafael de los Ríos Cristóbal Bartolini Manuela Andrisano Vincenza Iriepa Isabel Moraleda Ignacio Gálvez Enrique García Manuela Egea Javier Samadi Abdelouhaid Chioua Mourad Marco-Contelles José |
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Affiliation: | aResearch Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal;bLaboratorio de Radicales Libres y Química Computacional (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain;cInstituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo 4, 28029 Madrid, Spain;dDepartamento de Química Orgánica, Facultad de Farmacia, Universidad de Alcalá, Ctra. Barcelona, Km. 33.6, 28817 Alcalá de Henares, Spain;eInstituto de Investigación Sanitaria, Hospital Universitario de la Princesa, C/Diego de León, 62, 28006 Madrid, Spain;fDepartment of Pharmaceutical Sciences, Alma Mater Studiorum, University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy;gHospital La Paz Health Research Institute-IdiPAZ, Madrid, Spain |
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Abstract: | The synthesis and pharmacological analyses of a number of furo[2,3-b]quinolin-4-amine, and pyrrolo[2,3-b]quinolin-4-amine derivatives are reported. Thus, we synthesized diversely substituted tacrine analogues 1–11 and 12–16 by Friedländer-type reaction of readily available o-amino(furano/pyrrolo)nitriles with suitable and selected cycloalkanones. The biological evaluation of furanotacrines1–11 and pyrrolotacrine13 showed that these are good, in the micromolar range, and highly selective inhibitors of BuChE. In the furanotacrine group, the most interesting inhibitor was 2-(p-tolyl)-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-amine (3) [IC50 (eqBuChE) = 2.9 ± 0.4 μM; IC50 (hBuChE) = 119 ± 15 μM]. Conversely, pyrrolotacrines12 and 14 proved moderately equipotent for both cholinesterases, being 1,2-diphenyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinolin-4-amine (12) the most potent for the inhibition of both enzymes [IC50 (EeAChE) = 0.61 ± 0.04 μM; IC50 (eqBuChE) = 0.074 ± 0.009 μM]. Moreover, pyrrolotacrine 12, at concentrations as low as 300 nM can afford significant neuroprotective effects against Aβ-induced toxicity. Docking studies show that compounds 3 and 12 bind in the middle of the AChE active site gorge, but are buried deeper inside BuChE active site gorge, as a consequence of larger BuChE gorge void. All these data suggest that these new tacrine analogues could be used for the potential treatment of Alzheimer’s disease. |
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Keywords: | AChE/BuChE inhibitors Neuroprotection Alzheimer&rsquo s disease |
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